Anti-allergic composition containing zwitterionic bicyclic compounds

ABSTRACT

Zwitterionic bicyclic compounds are disclosed which are useful as anti-allergic, anti-inflammatory and/or cytoprotective agents and in the treatment of hyperproliferative skin disease. Pharmaceutical compositions and methods of treatment employing such compounds are also disclosed.

The present application is a continuation-in-part of copending U.S.application Ser. No. 760,196 filed July 29, 1985 now U.S. Pat. No.4,684,727.

BACKGROUND OF THE INVENTION

The present invention relates to certain zwitterionic bicyclic compoundsand to pharmaceutical compositions and methods of use employing suchcompounds.

An article by Bowman et al. entitled "The Synthesis of SomeDialkylamino-2-quinolones," Journal of the Chemical Society, pp.1350-1353 (1964), discloses certain1-alkyl-3-dialkylamino-4-hydroxy-2-quinolones. Mentioned in this articleare 3-dimethylamino-4-hydroxy-1-phenyl-2-quinolone and 1-benzyl-3dimethylamino-4hydroxy-2-quinolone. No utility is mentioned in thearticle for such compounds.

Certain other 3-amino substituted quinolones are disclosed in Kappe etal., Monatshefte fur Chemie, 99, pp. 2157-2166 (1968); Merchant et al.,Curr. Sci., 49(1), pp. 20-21 (1980); and Wittmann et al. Z.Naturforsch., B: Anorg. Chem., Org. Chem., 33B(12), pp. 1540-1546(1978).

SUMMARY OF THE INVENTION

The invention in its pharmaceutical composition aspect comprises acompound having the structural formula I ##STR1## or a pharmaceuticalacceptable salt or solvate thereof, in a combination with apharmaceutically acceptable carrier, wherein:

W and X may be the same or different and each independently represents--CH═ or --N═;

Z₁ and Z₂ are the same or different and each independently represents Oor S;

R¹, R², R³, R⁴ and R⁵ are the same or different and each may beindependently selected from the group consisting of H, alkyl having from1 to 12 carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynylhaving from 3 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbonatoms in the alkoxy portion and from 2 to 6 atoms in the alkyl portionthereof, hydroxyalkyl having from 2 to 8 carbon atoms, cycloalkyl havingfrom 3 to 8 carbon atoms, acyloxyalkyl having from 1 to 6 carbon atomsin the acyloxy portion and from 2 to 8 carbon atoms in the alkyl portionthereof, and --R⁶ --CO₂ R⁰ wherein R⁶ represents an alkylene grouphaving from 1 to 6 carbon atoms and R⁰ represents hydrogen or an alkylgroup having from 1 to 6 carbon atoms, with the provisos that the OH ofthe hydroxyalkyl group and the acyloxy of the acyloxyalkyl group are notjoined to the same carbon atom as another heteroatom and that, when R¹,R² and/or R³ are alkenyl or alkynyl, there is at least one carbon-carbonsingle bond between the nitrogen atom and the carbon-carbon double ortriple bond;

in addition, one of R¹, R² or R³ can be an aryl group or a heterocyclicgroup, either of which can be substituted with one to three substituentsY as defined below;

in further addition, two of R¹, R² and R³ can be joined together torepresent a ring which can contain from 2 to 8 carbon atoms, said ringoptionally containing a --O--, --S-- and/or --NR⁴ -- heteroatomic group(wherein R⁴ is as defined above) and/or optionally containing acarbon-carbon double bond, and said ring optionally being substitutedwith one to three additional substituents R⁷ which substituents may bethe same or different and are each independently selected from OH withthe proviso that OH is not on a carbon already joined to a hetero atom,--O--acyl having from 1 to 6 carbon atoms, hydroxyalkyl having from 1 to8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in eachalkyl portion thereof, alkyl having from 1 to 6 carbon atoms, alkenylhaving from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbonatoms, --COOR¹⁰ wherein R¹⁰ is H alkyl or aryl, or any two R⁷substituent groups may represent a hydrocarbon ring having from 4 to 8total carbon atoms; and

in still further addition, all three of R¹, R² and R³ can be joinedtogether to represent a polycyclic ring, which polycyclic ring canoptionally be substituted by one to three substituent groups R⁷ asdefined above;

m is an integer of from 0 to 3;

n is an integer of from 0 to 2;

Q represents an aryl or an aromatic heterocyclic group which canoptionally be substituted with 1 to 3 substituents Y as defined below;and

each Y substituent is independently selected from the group consistingof hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, NO₂, alkoxyhaving from 1 to 6 carbon atoms, trifluoromethyl, cyano, cycloalkylhaving from 3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbonatoms, alkynyloxy having from 3 to 6 carbon atoms, hydroxyalkyl havingfrom 1 to 6 carbon atoms, --S(O)_(n) --R⁸ (wherein R⁸ represents alkylhaving from 1 to 6 carbcn atoms and n is as defined above), --SO₂ NH₂,--CO--R⁹ (wherein R⁹ represents OH, --NH--R⁸ or --O--R⁸, where R⁸ is asdefined above), --O--B--COR⁹ (wherein B represents an alkylene grouphaving from 1 to 4 carbon atoms and R⁹ is as defined above), --NH₂,--NHCHO, --NH--CO--R⁹ (wherein R⁹ is as defined above, with the provisothat it is not hydroxy), --NH--COCF₃, --NH--SO₂ R⁸ (wherein R⁸ is asdefined above), and --NHSO₂ CF₃.

A preferred subgenus of compounds is represented by those compounds inwhich at least one of W and X is N. More preferably, W is CH and X is N.Moreover, at least one of Z₁ and Z₂ is preferably O and m and n arepreferably zero.

An additional preferred subgenus of compounds is represented by thestructural formula II ##STR2## wherein R¹, R², R³, Q, Z₁ and Z₂ are asdefined above. Preferably, at least one of Z₁ and Z₂ is O. In addition,Q is preferably an aryl group, which may be optionally substituted withone to three Y groups, more preferably, one or two Y groups.

The compounds of the invention, because of their zwitterionic character,provide good solubility in physiological fluids, such as blood, plasma,saliva, etc., and in general in polar solvents, such as water andethanol, which can be used in compositions for delivering the compoundsto patients. This characteristic is advantageous in that the compoundsare expected to be more easily absorbed gastrointestinally and thereforeprovide good activity when administered orally.

The invention in a first pharmaceutical method aspect is a method fortreating allergic reactions in a mammal which comprises administering ananti-allergic effective amount of the above-defined pharmaceuticalcomposition to the mammal.

The invention in a second pharmaceutical method aspect is a method fortreating inflammation in a mammal which comprises administering ananti-inflammatory effective amount of the above-defined pharmaceuticalcomposition to the mammal.

The invention in a third pharmaceutical method aspect is a method fortreating peptic ulcers in a mammal which comprises administering acytoprotective effective amount of the above defined pharmaceuticalcomposition to the mammal.

The invention in its chemical compound aspect is a compound having thestructural formula I as defined above with the proviso that3-dimethylamino-4-hydroxy-1-phenyl-2-quinolone and1-benzyl-3-dimethylamino-4-hydroxy-2-quinolone are excluded. In anotheraspect the compounds of the invention may have the structural formula Ias defined above with the provisos that --NR¹ R² R³ does not represent--NH(alkyl)₂ when m=0, n=0, W and X are both --CH═, Q=phenyl, Z₁ =O andZ₂ =O or when m=1, n=0,W and X are both --CH═, R⁴ and R⁵ are both H,Q=phenyl, Z₁ =O and Z₂ =O.

DETAILED DESCRIPTION OF THE INVENTION

The compounds employed in the present invention may be prepared from acompound of structural formula III: ##STR3## wherein R⁴, R⁵, Q, X, Y, W,Z₁, Z₂, m and n are as defined above and L is a substituent known tothose skilled in the art as a "leaving group."

Treatment of a compound of the formula III above with the amine compoundof the formula ##STR4## (wherein R¹, R², and R³ are as defined above)with heat in a suitable solvent, such as pyridine, dimethyl formamide,hexamethyl phosphoramide, 2,6-lutidine, dimethyl acetamide and the like,results in formation of the desired product of formula I. The reaction,depending upon the reactants chosen, can be performed at temperatures ofabout 60° C. up to the reflux temperature of the particular solvent.

For purposes of the invention, a "leaving group" is defined as asubstituent which may be displaced and carry a negative charge.Representative examples of suitable leaving groups include chloride,bromide, iodide, trifluoroacetoxy, methanesulfonyloxy,trifluoromethanesulfonyloxy, p-toluene-sulfonyloxy, -I⁺ -Ar, and thelike. A preferred leaving group is bromide.

The compound of formula IV above is generally a secondary or tertiaryamine, i.e., one in which at most one of the groups R¹, R² or R³ ishydrogen. Such materials are readily obtainable either commercially orby methods well known to one of ordinary skill in the art.

The intermediates of formula III above are either known or can beprepared from corresponding 3-unsubstituted derivatives which aredisclosed, for example, in U.S. Pat. No. 4,492,702, the disclosure ofwhich is incorporated herein by reference. For example, a compound ofthe formula (V) ##STR5## (wherein Q, R⁴, R⁵, Y, W, X, n and m are asdefined herein and R is any convenient alkyl group) may be reacted witha compound of structural formula VI

    CH.sub.3 CO.sub.2 R                                        (VI)

(wherein R is again, for example, an alkyl group) to directly producethe compounds of the formula VII ##STR6## This reaction is preferablyaccomplished by contacting the two reactants V and VI in the presence ofa base such as a metal alkoxide, e.g., potassium tertiary butoxide orthe like, at an elevated temperature, e.g., 60° to about 160° C., for asufficient time until the reaction is substantially completed. Thereaction is preferably conducted in an inert atmosphere such asnitrogen. Alternatively, the reaction may be conducted in the presenceof a non-reactive solvent such as toluene, xylene, etc.

The compounds of formula VII above can be reacted with a suitable agentto provide the leaving group in the three position on the ring. Forexample, direct bromination of the compound of formula VII above willprovide a compound of III above where L equals Br. As another example,reaction of the compound of VII above with iodosobenzene results in theformation of a compound of formula III where L is -I⁺ -Ph.

The compounds of formula I can also be prepared by reacting a compoundof formula V with a compound of formula VIII in the presence of a base:##STR7## wherein R and R' each independently represents alkyl or aryl.Suitable bases include, for example, NaH, potassium t-butoxide, etc.

Alternatively, a compound of formula V may be reacted with a compund offormula IX or X in the presence of a base (or an epoxide with thecompound of formula IX): ##STR8## wherein L¹ and L² may be the same ordifferent and each represents a leaving group such as halo and Rrepresents alkyl or aryl. The compound of formula XI is then reactedwith a compound of formula IV to form an intermediate of formula XIIwhich may be converted to the final product Ia use of a suitable basesuch as Li-N(Si(CH₃)₃)₂, sodium methoxide or potassium t-butoxide:##STR9## If one of R¹, R² and R³ in formula XII is H, then such H groupwill be removed when treated with base.

The compounds having structural formula I or Ia above wherein Z₁ and Z₂are oxygen may be converted to the corresponding compounds wherein Z₁and/or Z₂ are sulfur by known methods. For example, treatment withLawesson's Reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] inhot toluene will effect this conversion. The isomeric and tautomericforms can be purified by chromatography of the reaction mixture.

When utilized herein and in the appended claims the below listed termsare defined as follows:

halogen--fluorine, chlorine, bromine and iodine;

alkyl and alkoxy--comprise straight and branched carbon chains and,unless otherwise specified, contain from 1 to 6 carbon atoms;

alkenyloxy--comprise straight and branched carbon chains and, unlessotherwise specified, have from 3 to 8 carbon atoms and contain a carbonto carbon double bond;

alkynyloxy--comprise straight and branched carbon chains and, unlessotherwise specified, have from 3 to 8 carbon atoms and contain a carbonto carbon triple bond;

aryl--a carbocyclic group containing at least one benzene ring, with thearyl groups preferably containing from 6 to 15 carbon atoms, morepreferably being phenyl or Y-substituted phenyl, e.g., phenyl, naphthyl,indenyl, indanyl, 4-chlorophenyl, 4-fluorophenyl, etc.;

aromatic heterocyclic--cyclic groups having at least one O, S and/or Nheterogroup interrupting the ring structure and having a sufficientnumber of unsaturated carbon to carbon bonds, nitrogen to carbon bonds,etc., to provide aromatic character, with the aromatic heterocyclicgroups preferably containing from 4 to 14 carbon atoms, e.g., pyridyl,furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl,pyridazinyl, 1,2,4-triazinyl, benzofuranyl, indolyl, pyrazolyl,oxazolyl, etc. Many times such heterocyclic groups can be bonded viavarious positions on the ring and all such variations are contemplated,e.g. 2- or 3-furanyl, 2-, 3- or 4-pyridyl, etc.

The compounds of the invention contain a --(CR⁴ R⁵)_(m) --substituentwherein each R⁴ group and each R⁵ group may vary independently. Thus,for example, when m equals 2 the following patterns of substitution(wherein hydrogen and CH₃ are used to represent any substituent, R⁴ orR⁵,) are contemplated: --C(CH₃)₂ CH₂ --, --CH₂ C(CH₃)₂ --, --CH₂CH(CH₃)--, --CH(CH₃)CH₂ --, --(C(CH₃)H)₂ -- and the like. In additionwhen m equals 3, substituents such as --C(CH₃)₂ CH(C₂ H₅)--CH₂ --,--CH(CH₃)--CH₂ --CH(C₂ H₅)--, and --CH₂ --CH(i-C₃ H₇)CH(C₂ H₅)-- arealso contemplated.

The R¹, R² and R³ groups on the amino nitrogen in the compounds of theinvention can be the same or different. In some instances as notedabove, two of such groups or three of such groups may together representa heterocyclic ring system with the nitrogen of the amino group beingpart of such ring, e.g., a monocyclic or bicyclic ring. Examples ofsuitable --N⁺ R¹ R² R³ groups include a protonated primary amino group--N⁺ H₃ ; protonated secondary amino groups such as --N⁺ H₂ (CH₃), --N⁺H₂ (--CH₂ --CH═CH₂), --N⁺ H₂ (phenyl), --N⁺ H₂ (4-pyridyl), etc.;protonated tertiary amino groups such as --N⁺ H(CH₃)₂, --N⁺ H(CH₂ CO₂H)[C(CH₂ OH)₃ ], etc.; quaternary amino groups such as --N⁺ (CH₃)₃, --N⁺(CH₃)₂ (phenyl) etc.; and protonated tertiary or quaternary,heterocyclic amino groups containing the nitrogen atom in theheterocyclic ring such as pyrrolidinium, 1-methyl pyrrolidinium,piperidinium, 1-methyl piperidinium, ##STR10##

As noted above, the compounds of the invention may include one to threeY substituents on the bicyclic ring system. Also, the Q group mayinclude one or two Y substituents. In cases where there is more than onesuch Y substituent, they may be the same or different. Thus, compoundshaving combinations of different Y substituents are contemplated withinthe scope of the invention. Examples of suitable Y substituents includeOH, methyl, chloro, bromo, methoxy, cyclohexyl, allyloxy, 2-propynyloxy,hydroxyethyl, methylthio, methylsulfonyl, carboxy, acetoxy,N-methylaminocarbonyl, acetoxymethoxy, acetamido, methylsulfonamido andthe like.

Exemplary compounds within the scope of the present invention are:##STR11##

The compounds of the invention are zwitterionic or inner salts, i.e.,they are both positively and negatively charged. However,pharmaceutically acceptable salts of such compounds are alsocontemplated, i.e., pharmaceutically acceptable acid addition or basicsalts. Examples of suitable acid addition salts include the chloride(from hydrochloric acid), methyl sulfate (from methyl sulfuric acid)sulfate (from sulfuric ac:id) and bromide. Basic salts can be formedwhen at least one of R¹, R² and R³ is H. Examples of suitable basicsalts include sodium, potassium or calcium salts (from theircorresponding hydroxides).

The compounds of the invention of formula I can exist in unsolvated aswell as solvated forms, including hydrated forms, e.g., a hemihydrate.In general, the solvated forms, with pharmaceutically acceptablesolvents such as water, ethanol and the like are equivalent to theunsolvated forms for purposes of the invention.

Certain compounds of the invention may exist in isomeric and tautomericforms. The invention contemplates all such isomers and tautomers--theisomers both in pure form and in admixture, including racemic mixtures.

The compounds of the invention may be employed as anti-allergy agents inthe treatment of, for example, asthma, allergic or seasonal rhinitis,and/or chronic bronchitis.

The anti-allergy method of this invention is identified by tests whichmeasure a compound's inhibition of anaphylactic bronchospasm insensitized guinea pigs having antigen induced broncho-constriction.

In one such test procedure, male Hartley guinea pigs (250-300 g) aresensitized with 5 mg ovalbumin injected i.p. and 5 mg injected s.c. in 1ml saline on day 1 and 5 mg ovalbumin injected i.p. on day 4. Thesensitized animals are used 3-4 weeks later at which time they weigh450-500 g.

The sensitized guinea pigs are fasted overnight and the followingmorning are anesthetized with 0.9 ml/kg i.p. of dialurethane (0.1 g/mldiallylbarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane). Thetrachea are cannulated and the animals are ventilated by a Harvardrodent respirator at 50 strokes/minute with a stroke volume of 5 ml. Aside arm to the tracheal cannula is connected to a Harvard pressuretransducer to obtain a continuous measure of intratracheal pressurewhich is recorded on a Harvard polygraph. The jugular vein is cannulatedfor the i.v. administration of substances. The animals are challengedwith antigen (0.5% ovalbumin) as an aerosol generated from a DeVilbissModel 65 ultrasonic nebulizer and delivered through the tracheal cannulafor 30 seconds. Bronchoconstriction is measured as the peak increase inintratracheal pressure occuring within 5 minutes after antigenchallenge.

The sensitized guinea pigs are injected i.v. with 1 mg/kg propranolol, 5mg/kg indomethacin and 2 mg/kg mepyramine given together in a volume of1 ml/kg. Fifteen minutes later the animals are challenged with nebulizedovalbumin. Test compounds are administered orally 2 hours beforechallenge with ovalbumin. Suppression of anaphylactic bronchospasm isexpressed as a percent inhibition of the peak increase in intratrachealpressure by comparison to a vehicle-treated control group.

For example, the compound1-methyl-1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidinium-hydroxide,inner salt (Compound A) was found to inhibit anaphylactic bronchospasmsin such test procedure when given at an oral dose of 1 mg/kg. Thiscompound was also found to inhibit allergen-induced histamine releasefrom guinea pig and human sensitized tissue. The compounds are effectivenon-adrenergic, non-anticholinergic, antianaphylactic agents. Whenadministered orally they are active at doses from about 0.1 to 10 mg/kgof body weight; when administered parenterally, e.g., intravenously, thecompounds are active at dosages of from about 0.05 to 5 mg/kg bodyweight, when administered by inhalation (aerosol or nebulizer) thecompounds are active at dosages of about 0.25 to 5 mg per puff, one tofour puffs may be taken every 4 hours.

The compounds of this invention are also useful for the treatment ofinflammation. Thus, they are useful in the treatment of arthritis,bursitis, tendonitis, gout and other inflammatory conditions. Theanti-inflammatory use of the compounds of the present invention may bedemonstrated by the Reversed Passive Arthus Reaction (RPAR) Synovitistechnique as set forth below using male Lewis rats (obtained fromCharles River Breeding Laboratories) weighing 200-250 grams and the RPARPaw technique as also described below. The potency of the compounds isdetermined using indomethacin as the standard. On the basis of the testresults, an oral dosage range of about 5 milligrams per kilogram of bodyweight per day to about 50 milligrams per kilogram of body weight perday in divided doses taken at about 4 hour intervals is recommended.

The dosage to be administered and the route of administration dependsupon the particular compound used, the age and general health of thepatient and the severity of the inflammatory condition. Thus, the doseultimately decided upon must be left to the judgment of a trainedhealth-care practitioner.

RPAR Synovitis Technique

A Lewis rat is dosed orally with drug or placebo one hour prior tointravenous administration of 2.28 mg of bovine serum albumin (BSA) in0.2 cc of pyrogen-free saline followed by the intraarticular injectionof 0.54 mg of rabbit anti-BSA antibody in 0.03 cc of pyrogen-free salineinto one knee joint. The contralateral knee is injected with 0.03 cc ofpyrogen free saline. All injections are made with the animal under lightether anesthesia. Three hours later the rat is again dosed orally withdrug or placebo. All drug doses are split. That is, one-half of the doseis administered before lesion induction and one-half is administeredafter lesion induction.

The following morning (about 17 hours after lesion induction) the rat iskilled and both knee joints are exposed. The subpatellar areolar tissuewith attendant synovium is excised and weighed. Differences between theweight of antibody and saline injected knees are considered to representthe inflammatory response for each animal (delta synovial weight).Differences in delta synovial weight between lesion controls anddrug-treated rats are evaluated for statistical significance with ananalysis of variance. Relative potencies are determined with a linearregression analysis.

Reversed Passive Arthus Response (RPAR) PAW Animals, Materials andMethods

Male Lewis inbred albino rats weighing 180-200 grams obtained fromCharles River Breeding Laboratories are used in these experiments. Therats are housed 3 animals/cage and food and water are allowed adlibitum. The animals are numbered 1-3 in each cage and color marked foridentification purposes.

Drug and Reagent Preparation

All reagents and drugs are prepared just prior to the study.Crystallized and lyophilized bovine serum albumin (BSA), available fromSigma Chemical Company, is solubilized without shaking in cold, sterile,pyrogen-free saline (10 mg/ml). Lyophilized anti-bovine serum albumin(IgG fraction), obtained from Cappel Laboratories, is suspended insterile distilled water and diluted with cold, pyrogen-free saline (PFS)just prior to use. The final concentration of anti-bovine serum albuminis 0.5 mg/ml of PFS. Both BSA and anti-BSA solutions are iced duringuse. Drugs are suspended or solubilized in an aqueous solution of methylcellulose (MC) with an homogenizer just prior to administration.

Drug Administration and Induction of Inflammation

Groups of animals (6/group) are dosed with drug in MC by gavage oncedaily for 3 days. The last dose is administered one hour prior tosensitization with BSA. Controls are given MC alone and a drug-standardis usually included in each assay for verification purposes. Drugs areprepared and diluted so as to provide a dose for a 200 gram animal whichis equivalent to the mg/kg dose for each experiment. Thus each ratreceives an oral dose in a volume of approximately 2.0 cc. One hourafter the last dose the animals are lightly anesthetized with ether and"sensitized" by injection of 0.2 ml of PFS containing 1.0 mg of BSA intothe penile vein. One hour later, the animals are "challenged" in theright rear paw with subplantar injections of 0.2 ml of PFS containing0.1 mg of anti-BSA. Immediately after the subplantar injection, theright paw is dipped (up to the lateral maleolus) into the mercury wellof a plethysmograph. The volume of mercury displaced is converted toweight and recorded. This value is considered to be the control readingfor the animal. Paw volumes are subsequently recorded with aplethysmograph during the development of the inflammation at 2 and 4hours post-challenge.

Results

Results are expressed by the change in paw volume (Δ paw volume) fromthe control reading for each animal to that recorded 2 and 4 hourspost-challenge. All drug treated groups are compared to the MC controlfor significant differences with an analysis of variance. Differencesfrom control in drug-treated groups are expressed as percent change fromcontrol. For example, the compound 1-N-methyl-1-(1,2dihydro-4hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-morpholinium-hydroxide,inner salt, hemihydrate and1-N-methyl-1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidinium-hydroxide,inner salt, hemihydrate given at an oral dose of 25 mg/kg, inhibited thepaw edema by 86% and 78%, respectively at 2 hours and by 52% and 9%,respectively at 4 hours.

The compounds of this invention are also useful in the treatment ofpeptic ulcers. They display chemotherapeutic activity which enables themto relieve the symptoms of peptic ulcer disease, stress ulceration, andpromote healing of gastric and/or duodenal ulcers. The antiulceractivity of the compounds of this invention is identified by tests whichmeasure the cytoprotective effect in rats. The compounds are also usefulas conjunctive therapeutic agents for coadministration with suchantiinflammatory/analgesic agents as aspirin, indomethacin,phenylbutazone, ibuprofen, naproxen, tolmetin and other agents. Thecompounds of this invention prevent the untoward side effects ofirritation and damage to the gastrointestinal tract caused by suchagents.

The compounds of this invention are evaluated for their antiulceractivity characteristics by standard biological testing procedures suchas the indomethacin-induced ulcer and/or ethanol-induced ulcer assaysdetailed below:

Indomethacin-Induced Ulcer Assay

Male Charles River CD rats (240-260 g) are fasted overnight. The testcompound is administered orally in methyl cellulose vehicle (2 ml/kg) tothe animals one hour prior to indomethacin 10 mg/kg p.c. The rats aresacrificed by CO₂ asphyxiation 4 hours after indomethacin. The stomachsare examined under a magnifying glass for lesions (Chiu et al., Arch.Int. Pharmacodyn. Ther., 270 128, 1984). For instance, Compound A causeda marked reduction of indomethacin-induced ulcers. At 10 mg/kg p.o.ulcer incidence with this compound was 75% in comparison with 100% forthe indomethacin control. Moreover, the average lesion size was reducedfrom 14.6 (±3.0) mm in control animals to 1.8 (±0.5) mm in drug treatedanimals, i.e., an 88% reduction in lesion size.

Ethanol-Induced Ulcer Assay

Male Charles River CD rats weighing 250-280 g are fasted and deprived ofwater for 20 hours before the experiments. The test compound,homogenized in aqueous methyl cellulose vehicle, is administered orally30 minutes prior to oral administration of 1 ml of absolute ethanol. Onehour after ethanol, the rats are sacrificed and the stomachs excised.The stomachs are opened through the greater curvature and the length ofeach linear hemorrhagic lesion induced by ethanol is measured andsummated for each stomach. Results are expressed as the mean lesionlength (mm) per rat (±SE). The data are analyzed by Duncan's multiplerange test and a P value of <0.5 is considered significant. Compound Aat 3mg/kg p.o. reduced the incidence of ulcers from 100% (in controls)to 62%. In addition, the lesion length was reduced from 61.6 (±8) mm inthe control animals to 6.3 (±3) mm in drug treated animals.

The compounds of this invention are found to be effective at doses ofabout 0.05-50 mg/kg of body weight per day. Preferably the total dosagesare administered in 2-4 divided doses per day.

When administered parenterally, e.g. intravenously, the compounds areadministered at a dosage range of about 0.01-10 mg/kg of body weight insingle or multiple daily doses.

To treat peptic ulcer disease, and prevent and treat drug-inducedgastric ulceration, the active compounds of this invention can beadministered in unit dosage forms such as tablets, capsules, pills,powders, granules, sterile parenteral solutions or suspensions,suppositories, mechanical delivery devices, e.g. transdermal, and thelike.

The compounds of formula I are useful in the treatment ofhyperproliferative skin-disease, e.g., psoriasis, which utility may bedemonstrated by the Arachidonic Acid Mouse Ear Test described below.

Arachidonic Acid Mouse Ear Test, Materials and Methods

Charles River, female, CD, (SD) BR mice, 6 weeks old, are caged 8/groupand allowed to acclimate 1-3 weeks prior to use.

Arachidonic acid (AA) is dissolved in reagent grade acetone (2 mg/.01ml) and stored at -20° C. for a maximum of 1 week prior to use.Inflammatory reactions are induced by applying 10 μl of AA to bothsurfaces of one ear (4 mg total).

Test drugs are dissolved in either reagent grade acetone or aqueousethanol (only if insoluble in acetone) at the same doses selected byOpas et al., Fed. Proc. 43, Abstract 2983, p. 1927 (1984) and Young etal., J. Invest. Dermatol. 82, pp 367-371 (1984). These doses areemployed to ensure maximum responses and to overcome any difference intopical absorption which could occur with any drug applied in an aqueousethanol vehicle. The test drug is applied 30 minutes prior to challengewith AA.

The severity of the inflammation is measured as a function of increasedear weight. A 6 mm punch biopsy is removed 1 hour after AA challenge andweighed to the nearest 0.1 mg. Mean ± standard error and all possiblecomparisons are made via Duncan's Multiple Range Statistic. Forinstance, Compound A, when tested in the assay at a single dose of 0.5mg/ear, resulted in a 61% reduction of the severity of inflammation. Ata dose of 0.1 mg/ear, the same compound gave a 43% reduction.

When administered for the treatment of hyperproliferative skin disease,the compounds of formula I may be administered topically, orally,rectally or parenterally. When administered topically, the amount ofcompound administered varies widely with the amount of skin beingtreated, as well as with the concentration of active ingredient appliedto the affected area. When administered orally, the compounds of formulaI are effective for the treatment of hyperproliferative skin disease atdaily doses ranging from about 0.1 mg/kg to about 100 mg/kg, preferablyfrom about 5 mg/kg to about 50 mg/kg, which may be administered individed doses. When administered rectally, the compounds of formula Imay be administered in daily doses ranging from about 0.1 mg/kg to about100 mg/kg. When administered parenterally, the compounds of formula Iare effective for the treatment of hyperproliferative skin disease indaily doses ranging from about 0.1 mg/kg body weight to about 10 mg/kgbody weight which may be administered in divided doses.

As a result of the topical administration of a compound of formula I, aremission of the symptoms of the psoriatic patient, in most cases, canbe expected. Thus, one affected by psoriasis can expect a decrease inscaling, erythema, size of the plaques, pruritus and other symptomsassociated with psoriasis. The dosage of medicament and the length oftime required for successfully treating each individual psoriaticpatient may vary, but those skilled in the art of medicine will be ableto recognize these variations and adjust the course of therapyaccordingly.

Included within the invention are preparations for topical applicationto the skin whereby the compounds having structural formula I areeffective in the treatment and control of skin diseases characterized byrapid rates of cell proliferation and/or abnormal cell proliferation,e.g. psoriasis.

In a preferred method of carrying out the invention, a pharmaceuticalformulation comprising a compound of formula I together with anon-toxic, pharmaceutically acceptable topical carrier, usually inconcentrations in the range of from about 0.001 percent to about 10percent, preferably from about 0.1 percent to about 5 percent, isapplied several times daily to the affected skin until the condition hasimproved. Topical applications may then be continued at less frequentintervals (e.g. once a day) to control mitosis in order to preventreturn of severe disease conditions.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders or tablet disintegrating agents; it can also be an encapsulatingmaterial. In powders, the carrier is a finely divided solid which is inadmixture with the finely divided active compound. In the tablet theactive compound is mixed with carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5 or 10 toabout 70 percent of the active ingredient. Suitable solid carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethyl-cellulose, a low melting wax, cocoa butter and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets and capsulescan be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solution. Aqueous solutionssuitable for oral use can be prepared by adding the active component inwater and adding suitable colorants, flavors, stabilizing, sweetening,solubilizing and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, i.e., natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcelluloseand other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions. These particular solid form preparations aremost conveniently provided in unit dose form and as such are used toprovide a single liquid dosage unit. Alternatively, sufficient solid maybe provided so that after conversion to liquid form, multiple individualliquid doses may be obtained by measuring predetermined volumes of theliquid form preparation as with a syringe, teaspoon or other volumetriccontainer. When multiple liquid doses are so prepared, it is preferredto maintain the unused portion of said liquid doses at low temperature(i.e., under refrigeration) in order to retard possible decomposition.The solid form preparations intended to be converted to liquid form maycontain, in addition to the active material, flavorants, colorants,stabilizers, buffers, artificial and natural sweeteners, dispersants,thickeners, solubilizing agents and the like. The solvent utilized forpreparing the liquid form preparation may be water, isotonic water,ethanol, glycerine, propylene glycol and the like as well as mixturesthereof. Naturally, the solvent utilized will be chosen with regard tothe route of administration, for example, liquid preparations containinglarge amounts of ethanol are not suitable for parenteral use.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions and/oremulsions and can be included in a transdermal patch of the matrix orreservoir type as are conventional in the art for this purpose.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules and powders invials or ampoules. The unit dosage form can also be a capsule, cachet ortablet itself or it can be the appropriate number of any of these inpackaged form.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 mg to 100 mg according to the particularapplication and to the potency of the active ingredient. Thecompositions can, if desired, also contain other therapeutic agents.

The dosages may be varied depending upon the requirements of thepatient, the severity of the condition being treated and the particularcompound being employed. Determination of the proper dosage for aparticular situation is within the skill of the art. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired.

The following examples are intended to illustrate, but not to limit, thepresent invention.

EXAMPLE 1 Preparation of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one

A mixture of methyl-2-phenylamino nicotinate (75.2 g), n-butylacetate(700 mL) and potassium tert-butoxide (148 g) was stirred and heatedgradually to reflux. The mixture was refluxed for 16 hours, after whichtime it was cooled and poured into water (7 L) with stirring. Theresulting mixture was acidified to pH 5 with concentrated HCl when awhite solid precipitated. The product was filtered off and air dried.The solid product was then suspended in hexane (3 L), triturated,filtered and washed with fresh hexane. This purification process wasrepeated using ether (1.5 L). The product was dried to yield 48 g of thedesired product, m.p. 312°-314° C.

By a similar procedure, using modifications well known to one skilled inthe art, the starting materials

ethyl-2-(pyrazinylamino)-nicotinate,

ethyl-2-(4-pyrimidinylamino)-nicotinate,

ethyl-2-(3-(1,2,4-triazinylamino))-nicotinate, and

ethyl-2-(2-thienylmethylamino)-nicotinate

can to converted to

4-hydroxy-1-(2-pyrazinyl)-1,8-naphthyridin-2(1H)-one,

4-hydroxy-1-(4-pyrimidinyl)-1,8-naphthyridin-2(1H)-one,

4-hydroxy-1-(3-(1,2,4-triazinyl))-1,8-naphthyridin-2(1H)-one, and

4-hydroxy-1-(2-thienylmethyl)-1,8-naphthyridin-2(1H)-one, respectively.

EXAMPLE 2 Preparation of3-bromo-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one

To a suspension of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1 g)in CH₂ Cl₂ (20 mL) was added, dropwise and with stirring, a solution ofbromine (0.7 g) in CH₂ Cl₂ (5 mL). The mixture was stirred at roomtemperature overnight, after which time the product was filtered off,dried in air and recrystallized from acetonitrile to yield 0.87 g of theproduct, m.p. 280° C.

By employing a similar procedure to that described in Example 2 aboveusing simple modifications based on practices well-known to one skilledin the art, the compounds

4-hydroxy-1-(2-pyrazinyl)-1,8-naphthyridin-2(1H)-one,

4-hydroxy-1-(4-pyrimidinyl)-1,8-naphthyridin-2(1H)-one,

4-hydroxy-1-(3-(1,2,4-triazinyl))-1,8-naphthyridin-2(1H)-one, and

4-hydroxy-1-(2-thienylmethyl)-1,8-naphthyridin-2(1H)-one

can be converted to

3-bromo-4-hydroxy-1-(2-pyrazinyl)-1,8- naphthyridin-2(1H)-one,

3-bromo-4-hydroxy-1-(4-pyrimidinyl)-1,8-naphthyridin-2(1H)-one,

3-bromo-4-hydroxy-1-(3-(1,2,4-triazinyl))-1,8-naphthyridin-2(1H)-one,and

3-bromo-4-hydroxy-1-(2-thienylmethyl)-1,8-naphthyridin-2(1H)-one,respectively.

EXAMPLE 3 Preparation of1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-1-methyl-pyrrolidiniumhydroxide, inner salt

In dry pyridine (30 mL),3-bromo-4-hydroxy-1-phenyl-1,8-naphthyridin-2(lH)-one (10 g) wassuspended. N-methyl pyrrolidine (20 mL) was added to the suspension. Themixture was heated to 95°-100° C. with stirring, and was kept there forabout 33 hours. The product was evaporated under high vacuum to providea dark oil. This oil was slurried with 200 mL of CH₃ CN(40): H₂ O(60):CH₃ CO₂ H(1) and filtered. The solid residue on the filter was rinsedwith water and the filtrate was evaporated to remove most of the CH₃ CN.Reversed phase chromatography through an E. Merck RP-8 LoBar column,eluting with increasing concentrations of CH₃ CN in H₂ O (containing 1%CH₃ CO₂ H) gave a moderately pure product which was subjected to asecond chromatographic separation using the same conditions as above.Fractions containing the product were combined and evaporated to yield asolid which was recrystallized from CH₂ Cl₂ /isopropanol to yield thedesired product, m.p. 245°-250° C.

EXAMPLE 4 Preparation of1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-1-methyl-pyrrolidiniumchloride

1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-1-methyl-pyrrolidiniumhydroxide, inner salt (0.1 g) was dissolved in 0.1 N-HCl soluticn (38mL). The solution was concentrated under high vacuum to provide an oilwhich crystallized on the addition of isopropanol. The solid wasfiltered off and washed with isopropanol to yield the desiredhydrochloride salt, m.p. 195° C.

EXAMPLE 5 Preparation of1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidiniumhydroxide, inner salt

A solution of 3-bromo-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (2g) in a mixture of pyrrolidine (10 mL) and DMF (5 mL) was stirred andheated at 100° C. for 2 days. The resulting mixture was then cooled,diluted with CH₂ Cl₂ (100 mL) and filtered. The solid was trituratedwith hot CHCl₃, filtered, and dried to yield the desired product, m.p.282°-284° C.

Some of the product was purified by (1) dissolving in a minimum volumeof 2,2,2-trifluoroethanol and (2) precipitating by the addition of 4volumes of methanol. The pure product charred and decomposed when heatedabove 285° C.

EXAMPLE 6 Preparation of1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-4-hydroxy-piperidiniumhydroxide, inner salt

A solution of 3-bromo-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1g) in a mixture of 2,6-lutidine (5 mL) and 4-hydroxy-piperidine (3.12 g)was heated at 100° C. for 32 hours. The lutidine was removed byevaporation under high vacuum. The residue was dissolved in CH₃ CN(20):H₂ O(80): CH₃ CO₂ H(1) and separated by reversed phase preparative HPLC(Whatman Magnum 40 with Partisil 40/ODS-3). The fractions containing thedesired product were combined and evaporated to yield a partiallycrystalline material which was recrystallized from isopropanol to yieldthe desired product, m.p. 256°-258° C.

The following compounds were also prepared by the techniques similar tothose described above:

1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)quinuclidiniumhydroxide, inner salt, hemihydrate, m.p. 290° C.

1-methyl-1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-morpholiniumhydroxide, inner salt, hemihydrate, m.p. 248°-249° C.

1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-piperidiniumhydroxide, inner salt, hemihydrate, m.p. 261°-263° C. (decomp.).

1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-2-hydroxymethylpiperidinium hydroxide, inner salt, hemihydrate, m.p. 135°-138° C.

By employing procedures similar to those described above in Examples 3,4, 5 and 6 with simple modifications well known to one skilled in theart, the compounds

3-bromo-4-hydroxy-1-(2-pyrazinyl)-1,8- naphthyridin-2(1H)-one,

3-bromo-4-hydroxy-1-(4-pyrimidinyl)-1,8- naphthyridin-2(1H)-one,

3-bromo-1-(3-chlorophenyl)-4-hydroxy-1,8-naphthyridin-2(1H)-one,

3-bromo-4-hydroxy-1-(3-(1,2,4-triazinyl))-1,8-naphthyridin-2(1H)-one,and

3-bromo-4-hydroxy-1-(2-thienylmethyl)-1,8-naphthyridin-2(1H)-one

can be converted to

1-[1,2-dihydro-4-hydroxy-2-oxo-1-(2-pyrazinyl)-1,8-naphthyridin-3-yl]-1-methyl-pyrrolidiniumhydroxide, inner salt,

1-[1,2-dihydro-4-hydroxy-2-oxo-1-(4-pyrimidinyl)-1,8-naphthyridin-3-yl]-1-methylpiperidiniumhydroxide, inner salt,

1-[1-(3-chlorophenyl)-1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridin-3-yl]-1-methyl-pyrrolidinium hydroxide, inner salt, or1-[1-(3-chlorophenyl)-1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridin-3-yl]-piperidiniumhydroxide, inner salt, m.p., 258.5°-261° C.

1-[1,2-dihydro-4-hydroxy-2-oxo-1-(3-(1,2,4-triazinyl))-1,8-naphthyridin-3-yl]- pyrrolidinium hydroxide, inner salt,and

1-(1,2-dihydro-4-hydroxy-2-oxo-1-(2-thienylmethyl)-1,8-naphthyridin-3-yl]-piperidinium hydroxide, innersalt, respectively.

EXAMPLE 7 Preparation of1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyrindin-3-yl)-pyrrolidiniumhydroxide, inner salt

Step A: To a stirred solution of 25.45 g (0.11 M) ofmethyl-2-phenylamino-nicotinate in 160 mL of t-butyl methyl ether(tBuOMe) (dried over 3A° sieves) heated to 50° (under N₂) 19.5 mL(2.2×0.11 M) of hloroacetylchloride followed by 31 mL (4×0.11 M) ofpropylene oxide was added. The reaction mixture was heated at 50° C. for1.5 hours and then 300 mL tBuOMe was added. This solution (cooled toroom temperature) was washed with 200 mL H₂ O containing 9.37 g (0.11 M)of NaHCO₃ followed by 30 mL of saturated aqueous NaCl solution. At thisstage the product that crystallized out was dissolved in 100 mL CH₂ Cl₂and this CH₂ Cl₂ was mixed with tBuOMe solution. The solution, as is,was used for the next reaction.

Step B: To the above solution at room temperature under N₂, 37.2 mL(4×0.11 M) of pyrrolidine was added and this solution was gentlyrefluxed overnight. 9.3 mL (0.11 M) of pyrrolidine was added, and thereaction was refluxed for an additional two hours. This mixture wasdiluted with 600 mL tBuOMe and washed with 300 mL H₂ O and the aqueouslayers were back extracted with 200 mL tBuOMe. The combined organic(tBuOMe) layer was washed with 150 mL saturated aqueous NaCl soln.,dried over anhydrous Na₂ SO₄, and then concentrated in vacuum (oil pumpvacuum) to 64.6 g of a crude brown semisolid, which was the methyl esterof 2-[1-pyrrolidinyl acetyl]phenylamino]-3-pyridine carboxylic acid.

Step C: The solid from step B above was suspended in 600 mL of cold (0°C.) tBuOMe (dried over 3A° sieves) under N₂. To this cold stirredmixture, 27.5 g (2.2×0.11 M) potassium t-butoxide was added, thereaction mixture was stirred for 1 hour, and then it was quenched with15 mL (2.4×0.11 M) of glacial acetic acid.

The stirred reaction mixture was allowed to attain room temperature andthen 350 mL H₂ O was added to it. The resultant solid was filtered,washed with tBuOMe, H₂ O, a small amount of CH₂ Cl₂, acetone, and thenair dried to obtain 27.09 g of the white product1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidiniumhydroxide, inner salt. The crude product was crystallized from 300 mLCH₃ OH+16 mL conc. H₂ SO₄ at 50° C.+3 g carbon; filtered, diluted with575 mL H₂ O, cooled to 0° C. and filtered; and draft oven dried at 60°C. for about 18 hours to give 22.2 g (82%) of crystallized whiteproduct.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

We claim:
 1. A pharmaceutical composition useful for treating allergicreactions, inflammation, peptic ulcers and/or hyperproliferative skindisease comprising an antiallergic, antiinflammatory, cytoprotectiveand/or anti-hyperproliferative effective amount of a compound having thestructural formula I ##STR12## or a pharmaceutically acceptable salt orsolvate thereof, in combination with a pharmaceutically acceptablecarrier wherein:W and X may be the same or different and eachindependently represents --CH═ or --N═; Z₁ and Z₂ are the same ordifferent and each independently represents O or S; R¹, R², R³, R⁴ andR⁵ are the same or different and each may be independently selected fromthe group consisting of H, alkyl having from 1 to 12 carbon atoms,alkenyl having from 3 to 8 carbon atoms, alkynyl having from 3 to 8carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in the alkoxyportion and from 2 to 6 atoms in the alkyl portion thereof, hydroxyalkylhaving from 2 to 8 carbon atoms, cycloalkyl having from 3 to 8 carbonatoms, acyloxyalkyl having from 1 to 6 carbon atoms in the acyloxyportion and from 2 to 8 carbon atoms in the alkyl portion thereof, and--R⁶ --CO₂ R^(O) wherein R⁶ represents an alyklene group having from 1to 6 carbon atoms and R^(O) represents hydrogen or an alkyl group havingfrom 1 to 6 carbon atoms, with the provisos that the OH of thehydroxyalkyl group and the acyloxy of the acyloxyalkyl group are notjoined to the same carbon atom as another heteroatom, that at least oneof R¹, R² and R³ is not hydrogen and that, when R¹, R² and/or R³ arealkenyl or alkynyl, there is at least one carbon-carbon single bondbetween the nitrogen atom and the carbon-carbon double or triple bond;in addition, one of R¹, R² or R³ can be an aryl group containing 6 to 15carbon atoms or an aromatic heterocyclic group containing 3 to 14 carbonatoms, either of which can be substituted with one to three substituentsY as defined below; in further addition, two of R¹, R² adn R³ can bejoined together to represent an imidazolyl ring or to represent a ringwhich can contain from 2 to 8 carbon atoms, said ring optionallycontaining a --O--, --S-- and/or --NR⁴ -- heteroatomic group (wherein R⁴is as defined above) and/or optionally containing a carbon-carbon doublebond, and said ring optionally being substituted with one to threeadditional substituents R⁷ which substituents may be the same ordifferent and are each independently selected from OH with the provisothat OH is not on a carbon already joined to a hetero atom, --O--acylhaving from 1 to 6 carbon atoms, hydroxyalkyl having from 1 to 8 carbonatoms, alkoxyalkyl having from 1 to 6 carbon atoms in each alkyl portionthereof, alkyl having from 1 to 6 carbon atoms, alkenyl having from 3 to8 carbon atoms, alkynyl having from 3 to 8 carobn atoms, --COOR¹⁰wherein R¹⁰ is H, alkyl or aryl containing from 6-15 carbon atoms, orany two R⁷ substituent groups may represent a hydrocarbon ring havingfrom 4 to 8 total carbon atoms; in still further addition, all three ofR¹, R², and R³ can be joined together to represent a polycyclic ring,which polycyclic ring can optionally be substituted by one to threesubstituents groups R⁷ as defined above; m is an integer of from 0 ot 3;n is an integer of from 0 to 3; Q represents an aryl group containing 6to 15 carbon atoms or an aromatic heterocyclic group containing 3 to 14carbon atoms, either of which group can optionally be substituted with 1to 3 substituents Y as define below; each Y substituent is independentlyselected from the group consisting of hydroxy, alkyl having from 1 to 6carbon atoms, halogen, NO₂, alkoxy having from 1 to 6 carbon atoms,trifluoromethyl, cyano, cycloalkyl having from 3 to 7 carbon atoms,alkenyloxy having from 3 to 6 carbon atoms, alkynyloxy having 3 to 6carbon atoms, hydroxyalkyl having from 1 to 6 carbon atoms, --S(O)_(n)--R⁸ (wherein R⁸ represents aklyl having from 1 to 6 carbon atoms and nis as defined above), --SO₂ NH₂, --CO--R⁹ (wherein R⁹ represents OH,--NH--R⁸ or --O--R⁸, where R⁸ is as defined above), --O--B--COR⁹(wherein B represents an alkylene group having from 1 to 4 carbon atomsand R⁹ is as defined above), --NH₂, --NHCHO, --NH--CO--R⁹ (wherein R⁹ isas defined above, with the proviso that it is not hydroxy), --NH--COCF₃,--NH--SO₂ R⁸ (wherein R⁸ is as defined above), and --NHSO₂ CF₃.
 2. Acomposition according to claim 1, wherein in the compound of formula Iat least one of W and X is --N═.
 3. A composition according to claim 1,wherein in the compound of formula I X is --N═ and W is --CH═.
 4. Acomposition according to claim 3, wherein in the compound of formula Iat least one of Z₁ and Z₂ is O.
 5. A composition according to claim 4,wherein in the compound of formula I Z₁ and Z₂ both are O.
 6. Acomposition according to claim 5, wherein in the compound of formula I nis
 0. 7. A composition according to claim 6, wherein in the compound offormula I m is
 0. 8. A composition according to claim 7, wherein in thecompound of fromula I Q is an aryl group, which may optionally besubstituted with one or two Y groups.
 9. A composition according toclaim 8, wherein in the compound of formula I Q is a phenyl group, whichmay optionally be substituted with one or two Y groups.
 10. Apharmaceutical composition useful for treating one or more diseasesselected from allergic reactions, inflammation, peptic ulcers andhyperproliferative skin disease comprising an antiallergic,antiinflammatory, cytoprotective and/or anti-hyperproliferativeeffective amount of a compound selectedfrom:1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-1-methyl-pyrrolidiniumhydroxide, inner salt;I-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidiniumhydroxide, inner salt;1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-4-hydoxy-piperidiniumhydroxide, inner salt;1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-quinuclidiniumhydroxide, inner salt;1-(2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-1-methyl-morpholiniumhydroxide, inner salt;1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-piperidiniumhydroxide, inner salt; or1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-2-hydroxymethyl-piperidiniumhydroxide, inner salt; or pharmaceutically acceptable salts thereof incombination with a pharmaceutically acceptable carrier.
 11. Apharmaceutical composition useful for treating one or more diseasesselected from allergic reactions, inflammation, peptic ulcers andhyperproliferative skin disease comprising an antiallergic,antiinflammatory, cytoprotective and/or anti-hyperproliferativeeffective amount of1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-1-methyl-pyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof, in combination with a pharmaceutically acceptable carrier. 12.A pharmaceutical composition useful for treating one or more diseasesselected from allergic reactions, inflammation, peptic ulcers andhyperproliferative skin disease comprising an antiallergic,antiinflammatory, cytoprotective and/or anti-hyperproliferativeeffective amount of1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)-pyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof in combination with a pharmaceutically acceptable carrier.
 13. Amethod for treating allergic reactions in a mammal which comprisesadministering to said mammal an anti-allergic effective amount of apharmaceutical composition containing as an active ingredient a compoundhaving the structural formula I ##STR13## or a pharmaceuticallyacceptable salt or solvate thereof, wherein: W and X may be the same ordiffernet and each independently represents --CH═ or --N═;Z₁ and Z₂ arethe same or differnet and each independently represents 0 or S; R¹, R²,R³, R⁴ and R⁵ are the same or different and each may be independentlyselected from the group consisting of H, alkyl having from 1 to 12carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl havingfrom 3 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms inthe alkoxy portion and from 2 to 6 atoms in the alkyl portion thereof,hydroxyalkyl having from 2 to 8 carbon atoms, cycloalkyl having from 3to 8 carbon atoms, acyloxyalkyl having from 1 to 6 carbon atoms in theacyloxy portion and from 2 to 8 carbon atoms in the alkyl portionthereof, and --R⁶ --CO₂ R^(O) wherein R⁶ represents an alyklene grouphaving from 1 to 6 carbon atoms and R⁰ represents hydrogen or an alkylgroup having from 1 to 6 carbon atoms, with the provisos that the OH ofthe hydroxyalkyl group and the acyloxy of the acyloxyalkyl group are notjoined to the same carbon atom as another heteroatom, that at least oneof R¹, R², and R³ is not hydrogen, and that when R¹, R² and/or R³ arealkenyl or alkynyl, there is at least one carbon-carbon single bondbetween the nitrogen atom and carbon-carbon double or triple bond; inaddition, one of R¹, R² or R³ can be can an aryl group containing 6 to15 carbon atoms or an aromatic heterocyclic group containing 3 to 14carbon atoms, either of which can be substituted with one to threesubstitutents y as defined below; in further addition, two of R¹, R² andR³ can be joined together ot represent an imidazolyl ring or torepresent a ring which can contain from 2 to 8 carobn atoms, said ringoptionally containing a --O--, --S-- and/or --NR₄ -- heteroatomic group(wherein R⁴ is as defined above) and/or optionally containing acarbon-carbon double bond, and said ring optionally being substitutedwith one to three additional substituents R⁷ which substitutents may bethe same or different and are each independently selected from OH withthe proviso that OH is not on a carbon already joined to a hetero atom,-O-acyl having from 1 to 6 carbon atoms, hydroxyalkyl having from 1 to 8carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in each alkylportion thereof, alkyl having from 1 to 6 carbon atoms, alkenyl havingfrom 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbon atoms,--COOR¹⁰ wherein R10 is H, alkyl or aryl containing from 6-15 carbonatoms, or any two R⁷ substituent groups may represent a hydrocarbon ringhaving from 4 to 8 total carbon atoms; in still further addition, allthree of R¹, R², and R³ can be joined together to represent a polycyclicring, which polycyclic ring can optionally be substittued by one tothree substituents groups R⁷ as defined above; m is an integer of from 0to 3; n is an integer of from 0 to 2; Q represents an aryl groupcontaining 6 to 15 carbon atoms or an aromatic hetrocylcic groupcontaining 3 to 14 carbon atoms, either of which group can optionally besubstituted with 1 to 3 substituents Y as defined below; each Ysubstituent is independently selected from the group consisting ofhydroxy, alkyl having from 1 to 6 carbon atoms, halogen, NO₂, alkoxyhaving from 1 to 6 carbon atoms, trifluoromethyl, cyano, cycloalkylhaving from 3 to 7 carbon atoms, akenyloxy having from 3 to 6 carbonatoms, alkynyloxy having 3 to 6 carbon atoms, hydroxyalkyl having from 1to 6 carbon atoms, --S(O)_(n) --R⁸ (wherein R⁸ represents akyl havingfrom 1 to 6 carbon atoms and n is as defined above), --SO₂ NH₂, --CO--R⁹(wherein R⁹ represents OH, --NH--R⁸ or --O--R⁸, where R⁸ is as definedabove), --O--B--COR⁹ (wherein B represents an alkylene group having from1 to 4 carbon atoms and R⁹ is as defined above), --NH₂, --NHCHO,--NH--CO--R⁹ (wherein R⁹ is as defined above, with the proviso that itis not hydroxy), --NH--COCF₃, --NH--SO₂ R⁸ (wherein R⁸ is as definedabove), and --NHSO₂ CF₃.
 14. A method for treating inflammation in amammal which comprises administering to said mammal an anti-inflammatoryeffective amount of a pharmaceutical composition containing as an activeigredient a compound having the structural formula I ##STR14## or apharmaceutically acceptable salt or solvate thereof, wherein: W and Xmay be the same or different and each independently represents --CH═ or--N═;Z₁ and Z₂ are the same or different and each independentlyrepresents O or S; R¹, R², R³, R⁴ and R⁵ are the same or different andeach may be independently selected from the group consisting of H, alkylhaving from 1 to 12 carbon atoms, alkenyl having from 3 to 8 carbonatoms, alkynyl having from 3 to 8 carbon atoms, alkoxyalkyl having from1 to 6 carbon atoms in the alkoxy portion and from 2 to 6 atoms in tehalkyl portion thereof, hydroxyalkyl having from 2 to 8 carbon atoms,cycloalkyl having from 3 to 8 carbon atoms, acyloxyalkyl having from 1to 6 carbon atoms in the acyloxy portion and from 2 to 8 carbon atoms inthe alkyl portion thereof, and --R⁶ --CO₂ R⁰ wherein R⁶ represents analyklene group having form 1 to 6 carbon atoms and R⁰ rerpesentshydrogen or an alkyl group having from 1 to 6 carbon atoms, with theprovisos that the OH of the hydroxyalkyl group and the acyloxy of theacyloxyalkyl group are not joined to the same carbon atom as anotherheteroatom and that when R¹, R² and/or R³ are alkenyl or alkynyl, thereis at least one carbon-carbon single bond between the nitrogen atom andthe carbon-carbon double or triple bond; in addition, one of R¹, R² orR³ can be an aryl group containing 6 to 15 carbon atoms or an aromaticheterocyclic group containing 3 to 14 carbon atoms, either of which canbe substituted with one to three substituents Y as defined below; infurther addition, two of R¹, R² and R³ can be joined together torepresent an imidazolyl ring or to represent a ring which can containfrom 2 to 8 carbon atoms, said ring optionally containing a --O--, --S--and/or --NR⁴ -- heteroatomic group (wherein R⁴ is as defined above)and/or optionally containing a carbon-carbon double bond, and said ringoptionally being substituted with one to three additional substituentsR⁷ which substitutuents may be the same or differnet and are eachindependently selected from OH with the proviso that OH is not on acarbon already joined to a hetero atom, --O-acyl having from 1 to 6carbon atoms, hydroxyalkyl having from 1 to 8 carbon atoms, alkoxyalkylhaving from 1 to 6 carbon atoms in each alkyl portion thereof, alkylhaving from 1 to 6 carbon atoms, alkenyl having from 3 to 8 carbonatoms, alkynyl having from 3 to 8 carbon atoms, --COOR¹⁰ wherein R¹⁰ isH, alkyl or aryl containing from 6-15 carbon atoms, or any two R⁷substituent groups may represent a hydrocarbon ring having from 4 to 8total carbon atoms; in still further addition, all three of R¹, R² andR³ can be joined together to represent a polycylic ring, whichpolycyclic ring can optionally be substituted by one to threesubstituents groups R⁷ as deifned above; m is an integer of from 0 to 3;n is an integer of from 0 to 2; Q represents an aryl group containing 6to 15 carbon atoms or an aromatic heterocyclic group containing 3 to 14carbon atoms, either of which group can optionally be substituted with 1to 3 subsitutents Y as defined below; each Y substituent isindependently selected from the group consisting of hydroxy, alkylhaving from 1 to 6 carbon atoms, halogen, NO₂, alkoxy having from 1 to 6carbon atoms, trifluoromethyl, cyano, cycloalkyl having from 3 to 7carbon atoms, alkenyloxy having from 3 to 6 carbon atoms, alkynyloxyhaving 3 to 6 carbon atoms, hydroxyalkyl having from 1 to 6 carbonatoms, --S(O)_(n) --R⁸ (wherein R⁸ represents alkyl having from 1 to 6carbon atoms and n is as defined above), --SO₂ NH₂, --CO--R⁹ (wherein R⁹represents OH, --NH--R⁸ or --O--R⁸, where R⁸ is as defined above),--O--B--COR⁹ (wherein B represents an alkylene group having from 1 to 4carbon atoms and R⁹ is as defined above), --NH₂, --NHCHO, --NH--CO--R⁹(wherein R⁹ is as defined above, with the proviso that it is nothydroxy), --NH--COCF₃, --NH--SO₂ R⁸ (wherein R⁸ is as defined above),and --NHSO₂ CF₃.
 15. A method for treating peptic ulcers in a mammalwhich comprises administering to said mammal a cytoprotective amount ofa pharmaceutical composition containing as an active ingredient acompound having the structural formula ##STR15## or a pharmaceuticallyacceptable salt or solvate thereof, wherein: W and X may be the same ordifferent and each independently represents --CH═ or --N═;Z₁ and Z₂ arethe same or different and each independently represents O or S; R¹, R²,R³, R⁴, and R⁵ are the same or different and each may be independentlyselected from the group consisting of H, alkyl having from 1 to 12carbon atoms, alkenyl having from 3 to 8 carbon atoms, alkynyl havingfrom 3 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms inthe alkoxy portion and from 2 to 6 atoms in the alkyl portion thereof,hydroxyalkyl having from 2 to 8 carbon atoms, cycloalkyl having from 3to 8 carbon atoms, acyloxyalkyl having from 1 to 6 carbon atoms in theacyloxy portion and from 2 to 8 carbon atoms in the alkyl portionthereof, and --R⁶ --CO₂ R⁰ wherein R⁶ represents an alyklene grouphaving from 1 to 6 carbon atoms and R⁰ represents hydrogen or an alkylgroup having from 1 to 6 carbon atoms, with the provisos that the OH ofthe hydroxyalkyl group and the acyloxy of the acyloxyalkyl group are notjoined to the same carbon atom as another heteroatom and that when R¹,R² and/or R³ are alkenyl or alkynyl, thereis at least one carbon-carbonsingle bond between the nitrogen atom and the carbon-carbon double ortriple bond; in addition, one of R¹, R² or R³ can be an aryl groupcontaining 6 to 15 carbon atoms or an aromatic heterocyclic groupcontaining 3 to 14 carbon atoms, either of which can be substituted withone to three substituents Y as defined below; in further addition, twoof R¹, R² and R³ can be joined together to represent an imidazolyl ringor to represent a ring which can contain from 2 to 8 carbon atoms, saidring optionally containing a --O--, --S-- and/or --NR⁴ -- heteroatomicgroup (wherein R⁴ is as defined above) and/or optionally containing acarbon-carbon double bond, and said ring optionally being substitutedwith one to three additional substituents R⁷ which substituents may bethe same or different and are each independently selected from OH withthe proviso that OH is not on a carbon already joined to a hetero atom,--O-acyl having from 1 to 6 carbon atoms, hydroxyalkyl having form 1 to8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms in eachalkyl portion thereof, alkyl having from 1 to 6 carbon atoms, alkenylhaving from 3 to 8 carbon atoms, alkynyl having from 3 to 8 carbonatoms, --COOR¹⁰ wherein R¹⁰ is H, alkyl or aryl containing from 6-15carbon atoms, or any two R⁷ substituent groups may represent ahydrocarbon ring having from 4 to 8 total carbon atoms; in still furtheraddition, all three of R¹, R² and R³ can be joined together to representa polycyclic ring, which polycyclic ring can optionally be substitutedby one to three substituents groups R⁷ as defined above; m is an integerof from 0 to 3; n is an integer of from 0 to 2; Q represents an arylgroup containing 6 to 15 carbon atoms or an aromatic heterocyclic groupcontaining 3 to 14 carbon atoms, either of which group can optionally besubstituted with 1 to 3 substituents Y as defined below; each Ysubstituent is indnependently selected from the group consisting ofhydroxy, alkyl having from 1 to 6 carbon atoms, halogen, NO₂, alkoxyhaving from 1 to 6 carbon atoms, trifluoromethyl, cyano, cycloalkylhaving from 3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbonatoms, alkynyloxy having 3 to 6 carbon atoms, hydroxyalkyl having from 1to 6 carbon atoms, --S(O)_(n) --R⁸ (wherein R⁸ represents alkyl havingfrom 1 to 6 carbon atoms and n is as defined above), --SO₂ NH₂, --CO--R⁹(wherein R⁹ represents OH, --HN--R⁸ or --O--R⁸, where R⁸ is as definedabove), --O--B--COR⁹ (wherein B represents an alkylene group having from1 to 4 carbon atoms and R⁹ is as defined above), --NH₂, --NHCHO,--NH--CO--R⁹ (wherein R⁹ is as defined above, with the proviso that itis not hydroxy), --NH--COCF₃, --NH--SO₂ R⁸ (wherein R⁸ is as definedabove), and --NHSO₂ CF₃.
 16. A method for treating a mammal sufferingfrom hyperproliferative skin disease which comprises administering tosaid mammal an anti-hyperproliferative effective amount of apharmaceutical composition containing as an active ingredient a compoundhaving the structural formula I ##STR16## or a pharmaceuticallyacceptable salt or solvate thereof, wherein: W and X may be the same ordiffernet and each independently represents --CH═ or --N═;Z₁ and Z₂ arethe same or different and each independently represents O or S; R¹, R²,R³, R⁴ and R⁵ are the same or different and each may be independentlyselected from the group consisting of H, alkyl having from 1 to 12carbon atoms, alkenyl havign from 3 to 8 carbon atoms, alkynyl havingfrom 3 to 8 carbon atoms, alkoxyalkyl having from 1 to 6 carbon atoms inthe alkoxy portion and from 2 to 6 atoms in the alkyl portion thereof,hydroxyalkyl having from 2 to 8 carbon atoms, cycloalkyl having from 3to 8 carbon atoms, acyloxyalkyl having from 1 to 6 carbon atoms in theacyloxy portion and from 2 to 8 carbon atoms in the alkyl portionthereof, and --R⁶ --CO₂ R⁰ wherein R⁶ represents an alyklene grouphaving from 1 to 6 carbon atoms and R⁰ represents hydrogen or an alkylgroup having from 1 to 6 carbon atoms, with the provisos that the OH ofthe hydroxyalkyl grop and the acyloxy of the acyloxyalkyl group are notjoined to the same carbon atom as another heteroatom and that when R¹,R², and/or R³ are alkenyl or alkynyl, there is at least onecarbon-carbon single bond between the nitrogen atom and thecarbon-carbon double or triple bond; in addition, one of R¹, R² or R³can be an aryl group containing 6 to 15 carbon atoms or an aromaticheterocyclic group containing 3 to 14 carbon atoms, either of which canbe substituted with one to three substituents Y as defined below; infurther addition, two of R¹, R² and R³ can be joined together torepresent an imidazolyl ring or to represent a ring which can containfrom 2 to 8 carbon atoms, said ring optionally containing a --O--, --S--and/or --NR⁴ -- heteroatomic group (wherein R⁴ is as defined above)and/or optionally containing a carbon-carbon double bond, and said ringoptionally being substituted with one to three additional substitutentsR⁷ which substituents may be the same or different and are eachindependently selected from OH with the proviso that OH is not on acarbon already joined to a hetero atom, --O-acyl having from 1 to 6carbon atoms, hdroxyalkyl having from 1 to 8 carbon atoms, alkoxyalkylhaving from 1 to 6 carbon atoms in each alkyl portion thereof, alkylhaving from to 1 to 6 carbon atoms, alkenyl having from 3 to 8 carobnatoms, alkynyl having from 3 to 8 carbon atoms, --COOR¹⁰ wherein R¹⁰ isH, akyl or aryl containing from 6-15 carbon atoms, or any two R⁷substituent groups may represent a hydrocarbon ring having from 4 to 8total carbon atoms; in still further addition, all three of R¹, R² andR³ can be joined together to represent a polycyclic ring, whichpolycyclic ring can optionally be substituted by one to threesubstituents groups R⁷ defined above; m is an integer of from 0 to 3; nis an integer of from 0 to 2; Q represents an aryl containing 6 to 15carbon atoms or an aromatic heterocyclic group containing 3 to 14 carbonatoms, either of which group can optionally be substituted with 1 to 3substitutents Y as defined below; each Y substituent is independentlyselected from the group consisting of hydroxy, alkyl having from 1 to 6carbon atoms, halogen, NO₂, alkxoy having from 1 to 6 carbon atoms,trifluoromethyl, cyano, cycloalkyl having from 3 to 7 carbon atoms,alkenyloxy having from 3 to 6 carbon atoms, alkynyloxy having 3 to 6carbon atoms, hydroxyalkyl having from 1 to 6 carbon atoms, --S(O)_(n)--R⁸ (wherein R⁸ represents alkyl having from 1 to 6 carbon atoms and nis as defined above), --SO₂ NH₂, --CO--R⁹ (wherein R⁹ represents OH,--NH--R⁸ or --O--R⁸, where R⁸ is as defined above), --O--B--COR⁹(wherein B represents an alkylene group having from 1 to 4 carbon atomsand R⁹ is as defined above), --NH₂, --NHCHO, --NH--CO--R⁹ (wherein R⁹ isas defined above, with the proviso that it is into hydroxy),--NH--COCF₃, --NH--SO₂ R⁸ (wherein R⁸ is as defined above), and --NHSO₂CF₃.
 17. A method according to claim 13, wherein in the compound offormula I at least one of W and X is --N═.
 18. A method according toclaim 13, wherein in the compound of formula I X is --N═ and W is --CH═.19. A method according to claim 14, wherein in the compound of formula Iand least one of W and X is --N═.
 20. A method according to claim 14,wherein in the compound of formula I X is --N═ and W is --CH═.
 21. Amethod according to claim 15, wherein in the compound of formula I atleast one of W and X is --N═.
 22. A method according to claim 15,wherein in the compound of formula I, X is --N═ and W is --CH═.
 23. Amethod according to claim 16, wherein in the compound of formula I atleast one of X and W is --N═.
 24. A method according to claim 16,wherein in the compound of formula I X is --N═ and W is --CH═.
 25. Amethod according to claim 13, wherein the active ingredient is acompound of formula II ##STR17## or a pharmaceutically acceptable saltor solvate thereof, wherein R¹, R², R³, Q, Z₁ and Z₂ are as defined inclaim
 13. 26. A method according to claim 25, wherein Z₁ and Z₂ are bothO and Q represents a phenyl group, which may optionally be substitutedwith one or two Y groups.
 27. A method according to claim 25, whereinthe active ingredient is1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl-1-methylpyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof.
 28. A method according to claim 25, wherein the activeingredient is1-(1,2-dihydrol-4-hydroxy-1-phenyl-2-oxo-,18-naphthyridin-3-yl)pyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof.
 29. A method according to claim 14, wherein the activeingredient is a compound of formula II ##STR18## or a pharmaceuticallyacceptable salt or solvate thereof, wherein R¹, R², R³, Q, Z₁ and Z₂ areas defined in claim
 14. 30. A method according to claim 29, wherein Z₁and Z₂ are both O and Q represents a phenyl group, which may optionallybe substituted with one or two Y groups.
 31. A method according to claim29, wherein the active ingredient is1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl-1-methylpyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof.
 32. A method according to claim 29, wherein the activeingredient is1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)pyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof.
 33. A method according to claim 15, wherein the activeingredient is a compound of formula II ##STR19## or a pharmaceuticallyacceptable salt or solvate thereof, wherein R¹, R², R³, Q, Z₁ and Z₂ areas defined in claim
 15. 34. A method according to claim 33, wherein Z₁and Z₂ are both O and Q represents a phenyl group, which may optionallybe substituted with one or two Y groups.
 35. A method according to claim33, wherein the active ingredient is1-(1,2-dihdyro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl-1-methylpyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof.
 36. A method according to claim 33, wherein the activeingredient is1-(1,2-dihydro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)pyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof.
 37. A method according to claim 16, wherein the activeingredient is a compound of formula II ##STR20## or a pharmaceuticallyacceptable salt or solvate thereof, wherein R¹, R², R³, Q, Z₁ and Z₂ areas defined in claim
 16. 38. A method according to claim 37, wherein Z₁and Z₂ are both O and Q represents a phenyl group, which may optionallybe substituted with one or two Y groups.
 39. A method according to claim37, wherein the active ingredient is1-(1,2-dihdyro-4-hydroxy-1-phenyl-2-oxo-1,8-naphthyridin-3-yl-1-methylpyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof.
 40. A method according to claim 37, wherein the activeingredient is1-(1,2-dihydro-4-hydroxyl-1-phenyl-2-oxo-1,8-naphthyridin-3-yl)pyrrolidiniumhydroxide, inner salt or a pharmaceutically acceptable salt or solvatethereof.